Effective management of both acute and chronic pain continues to be an unmet need in medicine. Pain affects a large percentage of especially the older population. Besides having a significant impact on quality of life, pain has an enormous economic impact, both in terms of direct health care costs and in lost economic productivity. Strategies to alleviate pain should ideally target the localized pain generator or pain pathway along which the nociceptive signal is being transmitted. The most common pain management options (pharmacological) are systemic rather than addressing the specific pain pathway involved, have significant CNS side effects, and/or have high addiction potential (opiates). Regional anesthesia and peripheral nerve blocks avoid many of these side effects, but still require pharmaceutical agents that block all nerve activity in the region to which they ae applied. As alternatives to pharmaceutical approaches, nerve transections can be performed, or pain modulators based on implanted central or peripheral electrodes may be used, although both are associated with numerous undesirable side effects. Electrode-based techniques use overstimulation or inhibition of nociceptive neural pathways by injection of electrical currents ino the tissue. While potentially effective, implanted electrodes are relatively nonselective (and thu typically stimulate noninvolved neural pathways), and can migrate or break, resulting in loss of analgesic efficacy and requiring surgical correction with attendant risks. We propose to develop a novel, non-pharmacological approach to manage both acute and chronic neuropathic pain, without systemic side effects or risk of addiction. The proposed approach is based on our work with infrared nerve stimulation (INS). We have previously shown that pulsed infrared laser light has the ability to induce action potentials in excitable tissues. INS can have greater spatial specificity than electrical stimulation, and it has been shown that this technology can be used safely in both acute and chronic settings without causing thermal damage (histologically) or functional deficits. Using parameters different than those used in INS, infrared light is also abl to prevent the initiation of action potentials and can block the propagation of existing action potentials in a dose dependent fashion. Here we will develop optical nerve inhibition as a means of precise (i.e. blocking only the necessary portion of a nerve) and non-pharmacological nerve inhibition for modulating neural activity, thereby inhibiting both acute and chronic pain. We have coined the name PAIN (Photonic Analgesia by Inhibition of Nerves) for this novel technology. The goals of the proposed work are (1) to optimize the spatial and temporal laser parameters that will result in efficient, reliable and safe blocking of nerve conduction propagation; and 2) demonstrate the efficacy and safety of a photonic pain modulation device. To achieve these goals we will pursue the following specific aims: 1) determine the full optical parameter space (wavelength, radiant exposure, pulse duration, pulse frequency) for effective, reliable, and safe optical inhibition of nerve activity and distinguish this from parameters used fr INS or those that may elicit a pain response. As a function of these parameters we will determine the spatial specificity of PAIN, its ability to switch elements on or off, and develop technology to do so for multiple units; 2) based on physiological testing, extensive multi-physics numerical modeling and current work on creating laser-based implants for other applications, we will develop a prototype 4-channel IR illumination device for feasibility testing in peripheral nerves and the spinal cord in acute preparations; 3) we will perform initial test for safety and efficacy of PAIN in an acute-pain animal (rat) model. Using the optimized parameters from aim 1 as starting point, we will validate and further refine the efficacy and safety of PAIN in this myelinated neuron model as stepping stone towards human feasibility; finally, 4) we demonstrate feasibility (efficacy and safety) in a small scale human study in patients with intractable, chronic pain.